In response to RFA DE-02-007, we submit this proposal, which seeks to develop novel approaches to the assessment of oral mucosal immunity in HIV+ individuals. Mucosal immunity plays a major role in the pathogenesis of HIV infection, progression to AIDS and persistence of the virus in the oral tissues. However, the paucity of studies in oral mucosa of human subjects with AIDS is detrimental to the development of better therapeutic strategies for the control of HIV infection. The hypothesis tested in this project is that both CCR5+ leukocytes, which are targets of HIV infection, and anti-viral effector cells reside primarily in mucosal tissues, including oral mucosa. Cytokines and chemokines produced by these cells shape the microenvironment of the oral mucosa, influencing entry, replication and persistence of the virus. To define the cytokine/chemokine profile of the oral mucosa and its changes during disease, we propose to perform a cross-sectional study including normal volunteers and three distinct cohorts of HIV+ individuals on HAART with the CD4+ T cell count of > 500/mm3 or <200/mm3 and untreated subjects with the count of >500/mm3. A minute biocatheter will be inserted into oral mucosa of these subjects to collect interstitial transudate for cytokine/chemokine profiling by multiplex technology. A mucosal biopsy will be taken for immunohistologic subtyping of immune cells present in oral mucosa. Immunostaining will define the ability of these immune cells to express cytokinesichemokines. Realtime RT-PCR for cytokine/chemokine mRNA will be performed. Saliva and peripheral blood will be evaluated simultaneously. The immunologic profiles in the oral mucosa and blood compartments will be characterized in relation to disease activity and viral load. These studies are expected to elucidate interactions between immune cells in oral mucosa and the role of HIV in altering the mucosal milieu, including immune reconstitution after HAART. A better understanding of oral immunity in normal and HIV-infected mucosa is important for the development of new antiviral therapies, including oral antiviral vaccines.